Mathematical modelling as a proof of concept for MPNs as a human inflammation model for cancer development

• Published in: PloS one Vol. 12; no. 8; p. e0183620
• Main Authors: Andersen, Morten, Sajid, Zamra, Pedersen, Rasmus K, Gudmand-Hoeyer, Johanne, Ellervik, Christina, Skov, Vibe, Kjær, Lasse, Pallisgaard, Niels, Kruse, Torben A, Thomassen, Mads, Troelsen, Jesper, Hasselbalch, Hans Carl, Ottesen, Johnny T
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 31.08.2017; Public Library of Science (PLoS)
• Subjects: Acute myeloid leukemia; Apoptosis; Biology and Life Sciences; Cancer; Carcinogenesis - genetics; Cell death; Cell proliferation; Clonal Evolution - genetics; Cloning; Crohns disease; Development and progression; Developmental stages; Disease Progression; Epidemiology; Evolution; Feedback; Genetic aspects; Haplotypes; Hematology; Hospitals; Humans; Immunology; Inflammation; Inflammation - genetics; Inflammation - pathology; Inflammatory diseases; Interferon; Intervention; Janus Kinase 2 - genetics; Leukemia; Mathematical analysis; Mathematical models; Medicine and Health Sciences; Metastasis; Models, Theoretical; Mutation; Myelofibrosis; Myeloid leukemia; Myeloproliferative disorders; Myeloproliferative Disorders - genetics; Myeloproliferative Disorders - pathology; Neoplasms; Neoplasms - genetics; Neoplasms - pathology; Neoplastic Stem Cells - pathology; Pathogenesis; Physiological aspects; Polycythemia Vera - genetics; Polycythemia Vera - pathology; Properties; Research and Analysis Methods; Risk factors; Stem cells; Studies; Thrombocythemia, Essential - genetics; Thrombocythemia, Essential - pathology; Tumors
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0183620

The chronic Philadelphia-negative myeloproliferative neoplasms (MPNs) are acquired stem cell neoplasms which ultimately may transform to acute myelogenous leukemia. Most recently, chronic inflammation has been described as an important factor for the development and progression of MPNs in the biological continuum from early cancer stage to the advanced myelofibrosis stage, the MPNs being described as "A Human Inflammation Model for Cancer Development". This novel concept has been built upon clinical, experimental, genomic, immunological and not least epidemiological studies. Only a few studies have described the development of MPNs by mathematical models, and none have addressed the role of inflammation for clonal evolution and disease progression. Herein, we aim at using mathematical modelling to substantiate the concept of chronic inflammation as an important trigger and driver of MPNs.The basics of the model describe the proliferation from stem cells to mature cells including mutations of healthy stem cells to become malignant stem cells. We include a simple inflammatory coupling coping with cell death and affecting the basic model beneath. First, we describe the system without feedbacks or regulatory interactions. Next, we introduce inflammatory feedback into the system. Finally, we include other feedbacks and regulatory interactions forming the inflammatory-MPN model. Using mathematical modeling, we add further proof to the concept that chronic inflammation may be both a trigger of clonal evolution and an important driving force for MPN disease progression. Our findings support intervention at the earliest stage of cancer development to target the malignant clone and dampen concomitant inflammation.